Glucotoxicity promotes aberrant activation and mislocalization of Ras-related C3 botulinum toxin substrate 1 [Rac1] and metabolic dysfunction in pancreatic islet β-cells: Reversal of such metabolic defects by metformin
| Autor: | DiAnna L. Hynds, Sartaj Baidwan, Anjaneyulu Kowluru, Anil Chekuri |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
CD36 Antigens Male rac1 GTP-Binding Protein Cancer Research Clinical Biochemistry Pharmaceutical Science Apoptosis medicine.disease_cause Rats Sprague-Dawley 0302 clinical medicine Insulin-Secreting Cells geography.geographical_feature_category Kinase Caspase 3 Antidiuretic Agents Middle Aged Islet Metformin Cell biology 030220 oncology & carcinogenesis medicine.drug Signal Transduction medicine.medical_specialty Recombinant Fusion Proteins Primary Cell Culture RAC1 Context (language use) Biology Article Proto-Oncogene Proteins c-myc 03 medical and health sciences Prenylation Internal medicine medicine Animals Humans Pharmacology Cell Nucleus geography Biochemistry (medical) Cell Biology Culture Media Rats 030104 developmental biology Endocrinology Glucose Gene Expression Regulation Oxidative stress |
| Popis: | Emerging evidence suggests that long-term exposure of insulin-secreting pancreatic β-cells to hyperglycemic (HG; glucotoxic) conditions promotes oxidative stress, which, in turn, leads to stress kinase activation, mitochondrial dysfunction, loss of nuclear structure and integrity and cell apoptosis. Original observations from our laboratory have proposed that Rac1 plays a key regulatory role in the generation of oxidative stress and downstream signaling events culminating in the onset of dysfunction of pancreatic β-cells under the duress of metabolic stress. However, precise molecular and cellular mechanisms underlying the metabolic roles of hyperactive Rac1 remain less understood. Using pharmacological and molecular biological approaches, we now report mistargetting of biologically-active Rac1 [GTP-bound conformation] to the nuclear compartment in clonal INS-1 cells, normal rat islets and human islets under HG conditions. Our findings also suggest that such a signaling step is independent of post-translational prenylation of Rac1. Evidence is also presented to highlight novel roles for sustained activation of Rac1 in HG-induced expression of Cluster of Differentiation 36 [CD36], a fatty acid transporter protein, which is implicated in cell apoptosis. Finally, our findings suggest that metformin, a biguanide anti-diabetic drug, at a clinically relevant concentration, prevents β-cell defects [Rac1 activation, nuclear association, CD36 expression, stress kinase and caspase-3 activation, and loss in metabolic viability] under the duress of glucotoxicity. Potential implications of these findings in the context of novel and direct regulation of islet β-cell function by metformin are discussed. |
| Databáze: | OpenAIRE |
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